Aqueous preparation containing oligopeptides and etherified cyclodextrin

ABSTRACT

The present invention relates to an aqueous pharmaceutical preparation of oligopeptides comprising an oligopeptide of the formula I, cyclo-(n-Arg-nGly-nAsp-nD-nE), and a partially etherified β-cyclodextrin having a water solubility of greater than 1.8 mg/ml of water, and to the preparation of the aqueous pharmaceutical preparation.

The present invention relates to an aqueous pharmaceutical preparationof oligopeptides of the formula I, comprising an oligopeptide and anetherified β-cyclodextrin having a water solubility of greater than 1.8mg/ml of water, and to the preparation of the aqueous pharmaceuticalpreparation.

The oligopeptides present in the preparation according to the inventionare cyclopeptides of the formula Icyclo-(n-Arg-nGly-nAsp-nD-nE)in which

-   D and E each, independently of one another, denote Gly, Ala, β-Ala,    Asn, Asp, Asp(OR), Arg, Cha, Cys, Gln, Glu, His, lle, Leu, Lys,    Lys(Ac), Lys(AcNH₂), Lys(AcSH), Met, NaI, Nle, Orn, Phe, 4-Hal-Phe,    homoPhe, Phg, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr or Val, where    the said amino acid radicals may also be derivatised,-   R denotes alkyl having 1-18 C atoms,-   Hal denotes F, CI, Br or I,-   Ac denotes alkanoyl having 1-10 C atoms, aroyl having 7-11 carbon    atoms or aralkanoyl having 8-12 C atoms,-   n denotes a hydrogen atom or an alkyl radical R, benzyl or an    aralkyl radical having 7-18 C atoms on the alpha-amino function of    the corresponding amino acid radical,    with the proviso that at least one amino acid radical has a    substituent n, where n denotes R, and where, if they are radicals of    optically active amino acids and amino acid derivatives, both the D    and L forms are included, and physiologically acceptable salts    thereof.

The oligopeptides of the formula I are described in EP 0 770 622 A2.Regarding the significance of the amino acids and substituents presentin the formula I and the preparation of the peptides, reference is madeto this specification.

The oligopeptides of the formula I act as integrin inhibitors,inhibiting, in particular, the interactions of the β₃- or β₅-integrinreceptors with endogenous ligands. The compounds exhibit an activityagainst the integrins α_(v)β₃, α_(v)β₅, α_(v)β₆ and α_(II)β₃, but alsoagainst α_(v)β₁ and α_(v)β₈ receptors. Blockage of the α_(v)β₃ andα_(v)β₆ receptors is of particular importance here. Prevention of thestimulation of α_(v)β₃ receptors by the endogenous ligand fibrinogenshould be mentioned in particular here.

The interactions described result, in particular, in inhibition ofangiogenesis, making the oligopeptides suitable for cancer therapy.Particular mention should be made here of the oligopeptide cilengitide,a cyclic pentapeptide with the chemical designationcyclo-(Arg-Gly-Asp-D-Phe-NMe-Val). Cilengitide is already in phase II ofclinical trials for the treatment of cancer diseases.

Like other peptides, the oligopeptides of the formula I are alsopreferably administered parenterally as an aqueous solution. For them tobe used therapeutically, aqueous solutions of the oligopeptides aretherefore necessary. The aqueous oligopeptide solutions employed forthis purpose should be matched to the particular therapy requirements,in particular they should comprise the active ingredient in the amountnecessary therapy and should have an adequate shelf life.

The treatment of tumour diseases requires parenteral administration ofrelatively large amounts of active ingredient. Owing to their peptidestructure, the oligopeptides have relatively good water solubility.Nevertheless, the relatively large amounts of active ingredientnecessary for the therapy result in relatively large volumes of activeingredient solution which are to be administered parenterally. These canthen no longer simply be injected, but instead must be infused.

Cilengitide, for example, has a saturation solubility in physiologicalsaline solution of about 19 mg/ml and can therefore, for therapeuticuse, be safely administered parenterally in a concentration of 15 mg/mldissolved in physiological saline solution. If, for example, a dose of1500 mg is necessary for therapy with cilengitide, a volume to beadministered of 100 ml arises. Volumes in this order of magnitude can nolonger simply be injected and must be infused, which is disadvantageous.

In order to reduce the respective volume of active ingredient solutionto be administered, it is desirable to increase the active ingredientcontent in the respective aqueous solution. Like other peptides, thesolubility of the oligopeptides is dependent on the pH of the respectivesolvent. A suitable solubility-increasing measure is therefore, inparticular, adjustment of the pH of the aqueous solvent to a value atwhich the oligopeptide has higher solubility. However, the pH valuesnecessary for this purpose are in a non-physiological range, which is tobe regarded as extremely critical with respect to parenteraladministration. Furthermore, a pH which differs greatly from thephysiological pH usually results in accelerated peptide degradation inaqueous solution, meaning that solutions of this type also have aninadequate shelf life.

Extensive attempts to increase the solubility of oligopeptides have notachieved the desired success. For example, it has unsuccessfully beenattempted to improve the solubility of cilengitide by addition ofphysiologically tolerated organic solvents, such as ethanol orpropanediol. The addition of surfactants, such as Cremophor andpolysorbate 80, likewise did not produce any significant improvement inthe solubility of cilengitide.

Although mixtures of citric acid, phosphate buffer and surfactantsenabled the solubility of cilengitide to be increased, these solutionswere, however, not stable on storage.

EP 0149 197 discloses that cyclodextrin ethers are able to increase thewater solubility of sparingly water-soluble medicaments. Inclusioncompounds are said to be formed here, with the medicaments penetratinginto the hydrophobic cavity of the cyclodextrin ring system. Aprerequisite for the ability of the medicaments into the cavity is thatthey also fit into the cavity. The medicaments must therefore also notexceed a certain spatial size. All the medicaments mentioned in EP 0 149197 are low-molecular-weight chemical compounds and have low solubilityin water. By contrast, the active ingredients in question are peptideswhich have relatively good solubility in water and in addition have acomparatively high molecular weight and consequently a relatively largespatial size.

The object of the present invention was therefore to provide an aqueouspreparation having an increased content of oligopeptides of the formulaI which is suitable for parenteral administration. The preparationshould not comprise any toxicologically unacceptable adjuvants andshould be stable over a relatively long time.

Surprisingly, a preparation which meets these requirements has beenfound in the form of a solution which, besides an oligopeptide of theformula I, comprises a β-cyclodextrin ether having a water solubility ofgreater than 1.8 mg/ml.

The preparation according to the invention can be stored for a period ofat least 6 months in a stable manner at refrigerator temperature (2-8°C.) and even at room temperature (25° C., 60% r.h.). Surprisingly, thepreparation according to the invention can also be stored in a stablemanner at elevated temperatures and atmospheric humidity levels, forexample for 3 months at a temperature of 30° C., 60% r.h. and for 4weeks at 40° C. and 75% r.h.

β-Cyclodextrin is an α1,4-linked cyclic oligosaccharide comprising 7glucose units which has a saturation solubility of 1.8 mg/ml in water atroom temperature. Each of the (anhydro)glucose units of β-cyclodextrincontains free hydroxyl groups in the 2-, 3-, and 6-position, each ofwhich may be etherified. If all or some of the free hydroxyl groups onthe glucose units are etherified with alkyl groups containing one ormore polar, i.e. readily water-soluble group(s), such as, for example, ahydroxyalkyl group, etherified β-cyclodextrins having increased watersolubility compared with pure β-cyclodextrin are formed. Suitablehydroxyalkyl groups which increase the water solubility are, forexample, hydroxyethyl or hydroxypropyl groups, which can be introducedinto the β-cyclodextrin by reaction of the β-cyclodextrin with thecorresponding alkylene oxides, such as ethylene oxide or propyleneoxide.

The ether substituents present are preferably hydroxyethyl and/orhydroxypropyl groups.

The aqueous pharmaceutical preparation preferably comprises partiallyetherified β-cyclodextrin, i.e. β-cyclodextrin in which only some of thehydroxyl groups of the anhydroglucose units are in etherified form.

Depending on the amount of alkylene oxide employed for theetherification in relation to the β-cyclodextrin, etherifiedβ-cyclodextrins having different degree of substitution are formed. Thedegree of substitution based on ether substitution is expressed below asthe molar degree of substitution (MS) and denotes the molar amount ofalkylene oxide employed per mole of (anhydro)glucose unit.

In accordance with the invention, the partially etherifiedβ-cyclodextrins present in the aqueous pharmaceutical preparation have amolar degree of substitution of between 0.2 and 10. Preference is givento etherified β-cyclodextrins having a molar degree of substitution ofbetween 0.2 and 2, particularly preferably having a molar degree ofsubstitution of between 0.5 and 0.8 and very particularly preferablyhaving a molar degree of substitution of about 0.58-0.73.

The oligopeptide present in the aqueous solution according to theinvention can be any of the oligopeptides covered by the above generalformula I. The oligopeptide present in the aqueous pharmaceuticalpreparation is preferably cyclo-(NMeArg-Gly-Asp-D-Phe-Val),cyclo-(Arg-Gly-Asp-DPhe-NMeVal), cyclo-(Arg-NMeGly-Asp-DPhe-Val),cyclo-(Arg-Gly-NMeAsp-DPhe-Val) or cyclo-(Arg-Gly-Asp-NMeDPhe-Val).Cilengitide is particularly preferably present. As already mentionedabove, cilengitide has the chemical designationcyclo-(Arg-Gly-Asp-D-Phe-NMe-Val).

If the aqueous preparation is not already isotonic due to the osmoticproperties of the oligopeptide and due to the cyclodextrin, anisotonicity agent, preferably a physiologically tolerated salt, such as,for example, sodium chloride or potassium chloride, or a physiologicallytolerated polyol or a sugar, such as, for example, glucose or glycerolor mannitol, may furthermore be present in an amount necessary forestablishing isotonicity.

Furthermore, the aqueous preparation according to the invention maycomprise further physiologically tolerated adjuvants, such as, forexample, antioxidants, such as ascorbic acid or glutathione,preservatives, such as phenol, m-cresol, methyl- or propylparaben,chlorobutanol, thiomersal or benzalkonium chloride, or furtherstabilisers, structure formers and solubilisers, such as polyethyleneglycols (PEG), for example PEG 3000, 3350, 4000 or 6000, or dextrans.

In addition, the aqueous preparation according to the invention maycomprise buffers, where it is in principle possible for allphysiologically tolerated substances which are suitable for setting thedesired pH to be employed. Any buffer substance present is present in aconcentration of from 5 mmol/l to 50 mmol/l, preferably in aconcentration of from 10 to 20 mmol/l. Preferred buffers are citratebuffer or phosphate buffer. Suitable phosphate buffers are solutions ofthe mono- and/or disodium and potassium salts of phosphoric acid, suchas disodium hydrogenphosphate or potassium dihydrogenphosphate, andmixtures of the sodium and potassium salts, such as, for example,mixtures of disodium hydrogenphosphate and potassiumdihydrogenphosphate.

The aqueous preparation advantageously has a pH of from 5 to 8,preferably a pH of from 5.6 to 7.4, particularly preferably a pH of from6 to 7.2. The osmolality is preferably from 250 to 350 mOsmol/kg. Theaqueous preparation can thus be administered directly intravenously orintraarterially substantially without pain.

According to a preferred embodiment of the invention, the aqueouspharmaceutical preparation comprises from 20 to 120 mg/ml of cilengitideand from 15 to 25% by weight of hydroxypropyl-β-cyclodextrin having amolar degree of substitution of from 0.5 to 0.8.

According to a particularly preferred embodiment of the invention, theaqueous pharmaceutical preparation comprises about 80 mg/ml ofcilengitide and about 20% by weight of 2-hydroxypropyl-β-cyclodextrinhaving a molar degree of substitution of about 0.58-0.73.

The aqueous preparation can be prepared by dissolving the substancespresent in the preparation successively in water. In an advantageousmanner, firstly the cyclodextrin ether is dissolved in water, and theoligopeptide and any further adjuvants are subsequently added. Theinvention therefore also relates to a process for the preparation of theaqueous pharmaceutical preparation according to the invention which ischaracterised in that firstly the β-cyclodextrin ether is dissolved inwater, and the active ingredient and any further adjuvants aresubsequently added.

If necessary, the solution comprising the particular oligopeptide, theβ-cyclodextrin ether and any further adjuvants is set to a pH of from 5to 8. The solution is subsequently sterile-filtered.

The examples explain the invention without being restricted thereto.

EXAMPLE 1

Saturation Solubilities of the Oligopeptides with Reference to theExample of Cilengitide

In order to determine the saturation solubilities, the oligopeptide wasstirred for 1 hour at room temperature in the solvent indicated in eachcase. The results are shown in Table 1.

TABLE 1 Cilengitide Formulation [mg/ml] pH Water for injection purposes14.67 6.65 Ethanol/water (10% by vol. of ethanol) 6.68 6.63Ethanol/water (30% by vol. of ethanol) 3.91 6.90 Propanediol/water (10%by vol. of 13.44 6.79 propanediol) Propanediol/water (30% by vol. of12.54 7.01 propanediol) Propanediol/water (50% by vol. of 8.23 7.17propanediol) Phosphate buffer pH 1 106.10 1.23 Phosphate buffer pH 265.47 3.99 Phosphate buffer pH 3 22.48 4.79 Phosphate buffer pH 5 18.645.50 Phosphate buffer pH 7 17.98 6.98 0.9% NaCl solution in water 19.216.63 Citric acid/phosphate buffer, pH 2.5 83.86 3.85 Citricacid/phosphate buffer, pH 3 61.89 3.98 Citric acid/phosphate buffer, pH3.5 50.03 4.24 Citric acid/phosphate buffer, pH 3 83.19 4.14 with 0.5%of polysorbate 80 VS Citric acid/phosphate buffer, pH 3 73.14 4.09 with0.2% Cremophor RH 40 Citric acid/phosphate buffer, pH 3 71.48 4.33 with30% of glycerol Citric acid/phosphate buffer, pH 3 72.67 4.32 with 30%of glycerol and 0.5% of polysorbate 80 VS *pH of 80 mg of cilengitide in20% of 2-hydroxypropyl-β-cyclodextrin: 7.02

The results show that the saturation solubility of the oligopeptide inwater was not increased by the addition of the alcohols ethanol andpropanediol, but instead was impaired. By contrast, various buffermixtures in the acidic range produce a significant increase in thesaturation solubility. If surfactants are added to acidic solutions withincreased solubility for the oligopeptide, this does not result in afurther significant increase in solubility. If, instead of or inaddition to the surfactants, glycerol is added to the acidic solutions,even a reduction in the solubility is noted.

EXAMPLE 2

Stability of Selected Compositions from Example 1 with High SaturationSolubility for the Oligopeptide

Selected compositions in which cilengitide has a high saturationsolubility were stored for 8 and 26 weeks at 25° C., 60% r.h. and at 40°C. and 75% r.h. and analysed for their cilengitide content byhigh-pressure liquid chromatography (HPLC-UV) at the beginning (start)and after the storage time. The results are shown Table 2.

TABLE 2 Cilengitide content [%] Concentration 8 weeks 26 weeks ofcilengitide 25° C./ 40° C./75% Composition [mg/ml] Start 60% r.h. r.h.Citric acid phosphate 60 98.45 66.6 not measured buffer pH 3* Citricacid phosphate 60 98.43 66.77 not measured buffer pH 3 + 0.5%Polysorbate 80 VS* Citric acid phosphate 60 98.57 58.07 not measuredbuffer pH 2.5* Citric acid phosphate 60 98.97 67.07 not measured bufferpH 3 + 0.2% Cremophor RH 40* Citric acid phosphate 60 98.38 70.72 notmeasured buffer pH 3, isotonised with NaCl** Citric acid phosphate 6098.9 70.82 not measured buffer pH 3 + 0.2% Cremophor RH 40, isotonisedwith NaCl** Sodium chloride 15 98.87 99.2 98 isotonic* Citric acidphosphate 15 98.8 99 96.6 buffer pH 7, NaCl** NaCl, 15 98.47 98.6 95phosphate buffer pH 7** *formulation from Table 1 **additionalformulation to Table 1

None of the preparations with concentrations of 60 mg/ml of cilengitideexhibits adequate stability. Addition of Cremophor RH 40 or polysorbate80 VS does not result in better stability compared with the pure buffersolutions. The three tested preparations comprising 15 mg/ml ofcilengitide exhibit significantly better stabilities, with the isotonicNaCl solution being the most stable.

EXAMPLE 3

Saturation Solubilities of the Oligopeptides on Addition ofβ-Cyclodextrin Ethers

Analogously to Example 1, the effect of addition of β-cyclodextrinethers (MS 0.63) on the saturation solubilities of the oligopeptides wasdetermined using the example of cilengitide. The results are shown inTable 3.

TABLE 3 Concentration of cilengitide Formulation [mg/ml] pHWater/2-hydroxypropyl-β-cyclodextrin >90 7.02 (20%) (80 mg ofWater/2-hydroxypropyl-β-cyclodextrin >60 cilengitide in (15%) 20% of 2-Water/2-hydroxypropyl-β-cyclodextrin >40 hydroxypropyl- (10%)β-cyclodextrin)

The results show a significant increase in the solubility of cilengitidethrough addition of the β-cyclodextrin ethers. In contrast to theadditives tested in Example 1, the increase in solubility is directlyproportional to the concentration of β-cyclodextrin ether.

EXAMPLE 4

Aqueous preparation comprising:

-   200 mg of 2-hydroxypropyl-β-cyclodextrin (MS 0.63)-   80 mg of cilengitide-   to 1 ml of water for injection purposes

The stated amount of 2-hydroxypropyl-β-cyclodextrin was dissolved inabout 90% of the stated amount of water for injection purposes withstirring, the stated amount of oligopeptide was added, and, after aclear solution had been obtained, the remaining solvent was added. Theresultant solution was sterile-filtered, transferred into 6 ml vialseach containing 2 ml of solution, sealed with stoppers and crimped.

EXAMPLE 5

Comparative Stability Study of Preparations Comprising an Oligopeptidein Isotonic Saline Solution or in β-Cyclodextrin Ether Solution

The preparation in accordance with Example 4 and a preparation preparedanalogously comprising 15 mg/ml of cilengitide in isotonic salinesolution (0.9% of NaCl) were tested in stability studies. To this end,the aqueous preparations were stored at various temperatures for certaintimes and analysed using suitable analytical methods. Possibleinstabilities in the case of oligopeptides in aqueous solution areprincipally evident from the formation of rearrangement and hydrolysisproducts. In the case of cilengitide, the decomposition products stillcarry the same chromophores and, like the starting material, can bedetermined by HPLC-UV. The results are shown in Tables 4 to 6.

TABLE 4 Stability data at 2-8° C., 26 weeks Concentration Cilen- Com- ofcilengitide gitide Impurity Impurity Impurity position [mg/ml] (start)[%] 1 [%]* 2 [%] 3 [%] Isotonic 15 mg/ml 100.67   0.48 <0.05 <0.05 NaCl(start 0.43) 2- 80 mg/ml 99.13 <0.05 <0.05 <0.05 Hydroxy- propyl-β-cyclo- dextrin *Impurity 1 is specified with max. 2%.

TABLE 5 Stability data at 25° C./60% r.h., 26 weeks Concentration Cilen-Formu- of cilengitide gitide Impurity Impurity Impurity lation [mg/ml](start) [%] 1 [%] 2 [%] 3 [%] Isotonic 15 mg/ml 101.26 0.84 0.13 <0.05NaCl (start 0.43) 2- 80 mg/ml 96.56 0.39 0.14 <0.05 Hydroxy- propyl-β-cyclo- dextrin

TABLE 6 Stability data at 30° C./60% r.h., 26 weeks Concentration Cilen-Formu- of cilengitide gitide Impurity Impurity Impurity lation [mg/ml](start) [%] 1 [%] 2 [%] 3 [%] Isotonic 15 mg/ml 100.82 1.16 0.24 0.06NaCl (start 0.43) 2- 80 mg/ml 99.37 0.74 0.25 0.08 Hydroxy- propyl-β-cyclo- dextrin

Although the oligopeptide is present in the preparation in accordancewith Example 3 in a concentration more than 5 times higher than in thepreparation in isotonic saline solution, the preparation in accordancewith Example 3 comprising the β-cyclodextrin ether has similar stabilityto the preparation in isotonic saline solution.

Analytical Test Methods:

Appearance

The preparations prepared were checked visually for particles with theaid of a light source against a dark wall as described in Ph.Eur.

Assay and purity determination of cilengitide

The assay and purity determination was carried out with the aid of anHPLC-UV method at a wavelength of 215 nm. An RP 18 phase was used forthe separation. The eluent used was a pH 3.6 buffer consisting of sodiumdihydrogenphosphate and phosphoric acid, which was mixed in the sameproportion with acetonitrile. A gradient elution with varying proportionof additional acetonitrile was carried out.

1. An aqueous pharmaceutical composition comprising: an oligopeptide offormula Icyclo-(n-Arg-nGly-nAsp-nD-nE)  (I) in which D and E each, independentlyof one another, denote Gly, Ala, β-Ala, Asn, Asp, Asp(OR), Arg, Cha,Cys, Gln, Glu, His, Ile, Leu, Lys, Lys(Ac), Lys(AcNH₂), Lys(AcSH), Met,Nal, NIe, Orn, Phe, 4-Hal-Phe, homoPhe, Phg, Pro, Pya, Ser, Thr, Tia,Tic, Trp, Tyr or Val; R denotes alkyl having 1-18 C atoms; Hal denotesF, Cl Br or I; Ac denotes alkanoyl having 1-10 C atoms, aroyl having7-11 C atoms or aralkanoyl having 8-12 C atoms; and n denotes H, R,benzyl or aralkyl radical having 7-18 C atoms on the alpha-aminofunction of the corresponding amino acid, with the proviso that at leastone amino acid has a substituent n, where n denotes R, and where, if theamino acids are optically active, both the D and L forms are included,and physiologically acceptable salts thereof; and an etherifiedβ-cyclodextrin having a water solubility of greater than 1.8 mg/ml inwater.
 2. An aqueous pharmaceutical composition according to claim 1,wherein the etherified β-cyclodextrin present is a partially etherifiedβ-cyclodextrin.
 3. An aqueous pharmaceutical composition according toclaim 1, wherein the ether substituents in the etherified β-cyclodextrinare hydroxymethyl, hydroxypropyl, or combinations thereof.
 4. An aqueouspharmaceutical composition according to claim 1, wherein the etherifiedβ-cyclodextrin has a molar degree of substitution of between 0.2 and 10,based on the ether substituents.
 5. An aqueous pharmaceuticalcomposition according to claim 4, wherein the partially etherifiedβ-cyclodextrin has a molar degree of substitution of between 0.2 and 2,based on the ether substituents.
 6. An aqueous pharmaceuticalcomposition according to claim 4, wherein the partially etherifiedβ-cyclodextrin has a molar degree of substitution of between 0.5 and0.8, based on the ether substituents.
 7. An aqueous pharmaceuticalcomposition according to claim 1, wherein the oligopeptide iscilengitide.
 8. An aqueous pharmaceutical composition according to claim1, further comprising an isotonicity agent in an amount necessary forestablishing isotonicity.
 9. An aqueous pharmaceutical compositionaccording to claim 1, wherein said composition has a pH of from 5 to 8.10. An aqueous pharmaceutical composition according to claim 9, whereinsaid composition has a pH of from 6 to 7.2.
 11. An aqueouspharmaceutical composition according to claim 1, wherein saidoligopeptide is cilengitide and said etherified β-cyclodextrin is ahydroxypropyl-β-cyclodextrin having a molar degree of substitution offrom 0.5 to 0.8, and said composition contains from 20 to 120 mg/ml ofcilengitide and from 15 to 25% by weight of saidhydroxypropyl-β-cyclodextrin.
 12. An aqueous pharmaceutical compositionaccording to claim 11, wherein said composition contains about 80 mg/mlof cilengitide and about 20% by weight of hydroxypropyl-β-cyclodextrinhaving a molar degree of substitution of about 0.58-0.73.
 13. A processfor the preparation of an aqueous pharmaceutical preparation accordingto claim 1, said process comprising: dissolving the β-cyclodextrin etherin water, and then subsequently adding the oligopeptide and any furtheradjuvants.
 14. An aqueous pharmaceutical composition according to claim1, wherein said composition has a pH of from 5.6 to 7.4.
 15. An aqueouspharmaceutical composition according to claim 1, wherein saidcomposition has a pH of from 6 to 7.2. and the osmolality is from 250 to350 mOsmol/kg.
 16. An aqueous pharmaceutical composition according toclaim 2, wherein the ether substituents in the etherified β-cyclodextrinare hydroxymethyl, hydroxypropyl, or combinations thereof.
 17. Anaqueous pharmaceutical composition according to claim 4, wherein thepartially etherified β-cyclodextrin has a molar degree of substitutionof 0.58-0.73, based on the ether substituents.
 18. An aqueouspharmaceutical composition according to claim 1, wherein saidoligopeptide is cyclo-(NMeArg-Gly-Asp-D-Phe-Val),cyclo-(Arg-Gly-Asp-DPhe-NMeVal), cyclo-(Arg-NMeGly-Asp-DPhe-Val),cyclo-(Arg-Gly-NMeAsp-DPhe-Val), or cyclo-(Arg-Gly-Asp-NMeDPhe-Val). 19.An aqueous pharmaceutical composition according to claim 8, wherein saidisotonicity agent is a physiologically tolerated salt, physiologicallytolerated polyol, or a physiologically tolerated sugar.
 20. An aqueouspharmaceutical composition according to claim 19, wherein saidisotonicity agent is sodium chloride, potassium chloride, glucose,glycerol or mannitol.
 21. An aqueous pharmaceutical compositionaccording to claim 1, further comprising one or more physiologicallytolerated adjuvants selected from antioxidants, preservatives, andfurther stabilisers, structure formers and solubilizers, wherein thestabilisers, structure formers and solubilizers are selected from thegroup consisting of polyethylene glycols and dextrans.
 22. An aqueouspharmaceutical composition according to claim 1, further comprising oneor more physiologically tolerated buffers, present in a concentration offrom 5 mmol/l to 50 mmol/l.
 23. An aqueous pharmaceutical compositionaccording to claim 1, wherein the osmolality is from 250 to 350mOsmol/kg.